Mechanisms and treatment of COVID-19-associated acute kidney injury
Authors: Weibin Zhou, John Cijiang He
Journal: Molecular Therapy (2023)

Among the many complications of coronavirus disease 2019 (COVID-19), acute kidney injury (AKI) has been frequently observed in severe cases and is associated with high mortality. Proximal tubular injury is the primary renal manifestation in these patients,1Legrand M. Bell S. Forni L. Joannidis M. Koyner J.L. Liu K. Cantaluppi V. Pathophysiology of COVID-19-associated acute kidney injury.Nat. Rev. Nephrol. 2021; 17: 751-764https://doi.org/10.1038/s41581-021-00452-0Crossref PubMed Scopus (202) Google Scholar but recent reports have confirmed that both tubular cells and podocytes are susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Viral proteins have also been detected in the renal tubular cells of deceased patients with COVID-19.2Jansen J. Reimer K.C. Nagai J.S. Varghese F.S. Overheul G.J. de Beer M. Roverts R. Daviran D. Fermin L.A.S. Willemsen B. et al.SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids.Cell Stem Cell. 2022; 29: 217-231.e8https://doi.org/10.1016/j.stem.2021.12.010Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar,3Braun F. Lütgehetmann M. Pfefferle S. Wong M.N. Carsten A. Lindenmeyer M.T. Nörz D. Heinrich F. Meißner K. Wichmann D. et al.SARS-CoV-2 renal tropism associates with acute kidney injury.Lancet. 2020; 396: 597-598https://doi.org/10.1016/S0140-6736(20)31759-1Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar,4Diao B. Wang C. Wang R. Feng Z. Zhang J. Yang H. Tan Y. Wang H. Wang C. Liu L. et al.Human kidney is a target for novel severe acute respiratory syndrome coronavirus 2 infection.Nat. Commun. 2021; 12: 2506https://doi.org/10.1038/s41467-021-22781-1Crossref PubMed Scopus (205) Google Scholar,5Chen Z. Hu J. Liu L. Chen R. Wang M. Xiong M. Li Z.Q. Zhao Y. Li H. Guan C. et al.SARS-CoV-2 causes acute kidney injury by directly infecting renal tubules.Front. Cell Dev. Biol. 2021; 9: 664868https://doi.org/10.3389/fcell.2021.664868Crossref PubMed Scopus (17) Google Scholar Therefore, renal cytotoxicity conferred directly by viral proteins represents a potential pathogenic mechanism in these cases, in synergy with or even exacerbating the systemic response to viral infection that also injures the kidney. However, the precise molecular mechanism of kidney injury caused by this viral disease has remained unclear. In a pair of recent studies, researchers led by Dr. Hui Y. Lan focused on the mechanisms of the SARS-CoV-2 N protein in AKI and a potential treatment.6Wang W. Chen J. Hu D. Pan P. Liang L. Wu W. Tang Y. Huang X.R. Yu X. Wu J. Lan H.Y. SARS-CoV-2 N protein induces acute kidney injury via smad3-dependent G1 cell cycle arrest mechanism.Adv. Sci. 2022; 9: 2103248https://doi.org/10.1002/advs.202103248Crossref Scopus (29) Google Scholar,7Wu W. Wang W. Liang L. Chen J. Wei B. Huang X.R. Wang X. Yu X. Lan H.Y. Treatment with quercetin inhibits SARS-CoV-2 N protein-induced acute kidney injury by blocking Smad3-dependent G1 cell-cycle arrest.Mol. Ther. 2022; 2022https://doi.org/10.1016/j.ymthe.2022.12.002Abstract Full Text Full Text PDF Scopus (1) Google Scholar Since SARS-CoV and SARS-CoV-2 are both members of the beta coronavirus family and share a highly conserved genomic structure,8Kim D. Lee J.Y. Yang J.S. Kim J.W. Kim V.N. Chang H. The architecture of SARS-CoV-2 transcriptome.Cell. 2020; 181: 914-921.e10https://doi.org/10.1016/j.cell.2020.04.011Abstract Full Text Full Text PDF PubMed Scopus (1251) Google Scholar Lan and colleagues deduced that SARS-CoV-2 and SARS-CoV N proteins may also share functional similarity, i.e., disruption of transforming growth factor β (TGF-β) signaling. Indeed, the authors showed that the SARS-CoV-2 N protein can directly interact with Smad3 and promote Smad3 signaling induced by TGF-β or kidney injury, leading to Smad3-p21-dependent cell-cycle arrest and renal tubular cell necrosis in vitro and in vivo. They also demonstrated that inhibiting Smad3 genetically or pharmacologically effectively ameliorated the tubular cell injury elicited by the SARS-CoV-2 N protein, indicating a potential therapeutic target to treat COVID-19-associated kidney injury. Next, Lan and colleagues explored the protective effects of quercetin, a flavonoid purified from traditional Chinese medicine, in renal injury induced by the SARS-CoV-2 N protein.7Wu W. Wang W. Liang L. Chen J. Wei B. Huang X.R. Wang X. Yu X. Lan H.Y. Treatment with quercetin inhibits SARS-CoV-2 N protein-induced acute kidney injury by blocking Smad3-dependent G1 cell-cycle arrest.Mol. Ther. 2022; 2022https://doi.org/10.1016/j.ymthe.2022.12.002Abstract Full Text Full Text PDF Scopus (1) Google Scholar As aging and diabetes are two comorbidities of COVID-19-associated nephropathy,9Chen A. Yin L. Lee K. He J.C. Similarities and differences between COVID-19-associated nephropathy and HIV-associated nephropathy.Kidney Dis. 2022; 8: 1-12https://doi.org/10.1159/000520235Crossref Google Scholar the authors tested the therapeutic effects of quercetin in aged mice with diabetes and showed that quercetin could attenuate the renal injury caused by the SARS-CoV-2 N protein. Mechanistically, quercetin can block the binding of the N protein and Smad3, hence lifting the cell-cycle arrest and reducing renal tubular cell necrosis. Thus, this study has revealed a novel molecular mechanism of quercetin in targeted therapy for AKI in patients with COVID-19. Nonetheless, how quercetin interferes with the binding of the N protein via Smad3 requires additional research, such as determining the binding sites of quercetin in the N protein, as well as its affinity and specificity. Moreover, before these findings can be translated into humans, we need to know the potential toxicity of quercetin at the dose required for blocking the interaction between the N protein and Smad3. Many viral proteins have been shown to interact with host proteins and modulate various pathogenic signaling pathways in host cells. For example, nuclear factor κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) Signal TrASTAT3 signaling, which is involved in kidney cell injuries, can be enhanced by several viral proteins in SARS-CoV and SARS-CoV-2.10Cai H. Chen Y. Feng Y. Asadi M. Kaufman L. Lee K. Kehrer T. Miorin L. Garcia-Sastre A. Gusella G.L. et al.SARS-CoV-2 viral protein ORF3A injures renal tubules by interacting with TRIM59 to induce STAT3 activation.Mol Ther. 2022; (Dec 15)https://doi.org/10.1016/j.ymthe.2022.12.008Abstract Full Text Full Text PDF Scopus (4) Google Scholar Even though COVID-19 can cause a cytokine storm that exerts detrimental effects on kidney cells, the direct infection of kidney cells by SARS-CoV-2, albeit at a low rate, should be taken into consideration. The authors declare no financial interest.